1. Field of the Invention
The present invention relates to novel processes for producing N-[N-[3-(2-hydroxy-substituted phenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester derivatives which are important as sweeteners.
The present invention further relates to novel processes for producing high-purity products of N-[N-[3-(2-hydroxy-4-substituted phenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester derivatives which are especially important among the sweeteners described above. More specifically, the present invention relates to: (1) processes for purifying such derivatives which may contain various impurities; (2) processes for producing high-purity products of such derivatives using an especially excellent simple crystallization method; and (3) crystals of the derivatives which can be thus obtained.
Still further, the present invention relates to novel processes for producing various intermediates which are useful for the production of the foregoing derivatives, especially dialkoxychroman derivatives which have been found to be useful as production intermediates of aspartyl dipeptide ester derivatives (aspartame derivatives) that are especially excellent as sweeteners and have a high degree of sweetness. More specifically, it relates to processes for producing specific dialkoxychroman derivatives from resorcinol and an acrolein dialkyl acetal in two stages at good efficiency, and novel dialkoxychroman derivatives which can be obtained by such a process and are especially preferable intermediates.
2. Discussion of the Background
In recent years, the importance of good eating habits to health has been increasingly recognized, and especially fatness or obesity caused by an excessive intake of sugar and the diseases accompanied by the fatness have become an issue. Therefore, the development of a low-calorie sweetener that replaces sugar has been in demand. As a sweetener that is widely used at present, there is aspartame which is excellent in terms of safety and quality of sweetness. Nevertheless, it has been somewhat problematic in a stability. Under these circumstances, some of the present inventors have newly found N-[N-[3-(2-hydroxy-substituted phenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester derivatives to be sweeteners which are excellent in stability and very high in sweetness, namely superior in cost for sweetness in comparison with aspartame. N-[N-[3-(2-hydroxy-4-substituted phenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester derivatives are especially preferable, and N-[N-[3-(2-hydroxy-4-methoxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester is an even more preferable compound.
As a process for producing a foregoing novel N-[N-[3-(2-hydroxy-substituted phenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester derivative, a process which comprises reductively alkylating β-O-benzyl-α-L-aspartyl-L-phenylalanine methyl ester with 2-benzyloxy-substituted cinnamaldehyde derivative and NaB(OAc)3H, and then removing the benzyl group as a protecting group, and reducing of a double bond therein has been discovered by some of the present inventors. However, according to this process, the formation of the starting material is intricate, and further the reactions such as the reductive alkylation, the deprotection and the like have to be conducted separately. Thus, it requires steps that are somewhat intricate industrially.
Meanwhile, apart from the investigations of the present inventors, similar compounds in which an alkyl group is introduced into an amino group of the aspartic acid constituting aspartame have been studied, and are described in the Kokai publication of the International Patent Application No. WO94/11391. This publication describes N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester which is relatively similar in structure to the N-[N-[3-(2-hydroxy-substituted phenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester derivatives that the present inventors have found. However, a specific description of not only the starting material but also by what method the production was conducted is not provided at all in this publication.
Under these circumstances, the development of an industrially advantageous process for producing the foregoing derivative(s) has been in demand.
Thus, one problem to be solved by the present invention is to provide a practically and industrially advantageous process for producing N-[N-[3-(2-hydroxy-substituted phenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester derivatives that are excellent sweeteners having a high degree of sweetness.
Next, as stated above, an excellent process for purifying the derivatives which have newly been found by some of the present inventors as sweeteners having a high degree of sweetness is unknown.
As a process for purifying the novel N-[N-[3-(2-hydroxy-4-substituted phenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester derivative, for example, a process in which a reaction concentrated solution containing the desired compound of the present invention is purified by preparative thin layer chromatography (PTLC) has been employed. In this case, in the final form of the desired compound, extracted fractions of the desired compound are simply concentrated to dryness. Nevertheless, since this purification process involves silica gel column chromatography, when it is performed industrially, it incurs high costs and involves environmental problems such as waste silica gel and the like. Furthermore, when the final form of the desired compound is not a crystal but a mere solid, there is also the problem in view of a consumers' safety, such as decomposition after the delivery of the products or the like. Thus, a practical and industrial purification process of the desired compound is not at all established. Accordingly, the development of a process for producing the foregoing sweetener(s) having a high degree of sweetness in a state of a high purity, preferably in a crystallized state has been in demand.
Sweeteners are mainly used in foods or pharmaceuticals, and consumed by people. Thus, they have to be purified by a method which yields high-purity products actually free from impurity(ies) or decomposed substance(s). Moreover, in the case of peptide sweeteners which are relatively easily decomposable, such as the desired compounds of the present invention, a final form having a better stability is desired for preventing decomposition after the delivery of the products.
Therefore, the present inventors have conducted studies on the acquisition or the formation of high-purity products, especially crystals that are a better form in regard to stability as products, by purifying the desired compounds of the present invention through crystallization using a crystallization method.
Thus, another problem to be solved by the present invention is also to provide a practical and industrial process for purifying N-[N-[3-(2-hydroxy-4-substituted phenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester derivatives which are excellent as sweeteners and have a high degree of sweetness, especially a process for obtaining the high-purity desired compounds as crystals from impurity(ies) contained therein, and crystals which are a final form having better stability as products.
Moreover, further investigations of the present inventors have revealed that the development of an industrially superior process for producing the aspartyl dipeptide ester derivatives (aspartame derivatives) which are excellent as sweeteners and have a high degree of sweetness, especially the development of excellent intermediates which are useful for the production thereof is required.
Accordingly, another problem to be solved by the present invention is also to develop a process for producing the aspartyl dipeptide ester derivatives (aspartame derivatives) industrially and advantageously, and especially to provide compounds which are excellent as intermediates useful for the as production thereof and a simple process for producing the same.